Multicenter analysis of novel and established variables associated with successful human islet isolation outcomes.

Islet transplantation is a promising therapy used to achieve glycometabolic control in a select subgroup of individuals with type I diabetes. However, features that characterize human islet isolation success prior to transplantation are not standardized and lack validation. We conducted a retrospective analysis of 806 isolation records from 14 pancreas-processing laboratories, considering variables from relevant studies in the last 15 years. The outcome was defined as post-purification islet equivalent count, dichotomized into yields > or =315 000 or < or =220 000. Univariate analysis showed that donor cause of death and use of hormonal medications negatively influenced outcome. Conversely, pancreata from heavier donors and those containing elevated levels of surface fat positively influence outcome, as did heavier pancreata and donors with normal amylase levels. Multivariable logistic regression analysis identified the positive impact on outcome of surgically intact pancreata and donors with normal liver function, and confirmed that younger donors, increased body mass index, shorter cold ischemia times, no administration of fluid/electrolyte medications, absence of organ edema, use of University of Wisconsin preservation solution and a fatty pancreas improves outcome. In conclusion, this multicenter analysis highlights the importance of carefully reviewing all donor, pancreas and processing parameters prior to isolation and transplantation.

Validation of methodologies for quantifying isolated human islets: an Islet Cell Resources study.

BACKGROUND: Quantification of islet mass is a crucial criterion for defining the quality of the islet product ensuring a potent islet transplant when used as a therapeutic intervention for select patients with type I diabetes. METHODS: This multi-center study involved all eight member institutions of the National Institutes of Health-supported Islet Cell Resources Consortium. The study was designed to validate the standard counting procedure for quantifying isolated, dithizone-stained human islets as a reliable methodology by ascertaining the accuracy, repeatability (intra-observer variability), and intermediate precision (inter-observer variability). The secondary aim of the study was to evaluate a new software-assisted digital image analysis method as a supplement for islet quantification. RESULTS: The study demonstrated the accuracy, repeatability and intermediate precision of the standard counting procedure for isolated human islets. This study also demonstrated that software-assisted digital image analysis as a supplemental method for islet quantification was more accurate and consistent than the standard manual counting method. CONCLUSIONS: Standard counting procedures for enumerating isolated stained human islets is a valid methodology, but computer-assisted digital image analysis assessment of islet mass has the added benefit of providing a permanent record of the isolated islet product being evaluated that improves quality assurance operations of current good manufacturing practice.

Meeting the 12 lymph node (LN) benchmark in colon cancer.

BACKGROUND: Examining >or=12 LN in colon cancer has been suggested as a quality metric. The purpose of this study was to determine whether the 12 LN benchmark is achieved at NCCN centers compared to a US population-based sample. METHODS: Patients with stage I-III disease resected at NCCN centers were identified from a prospective database (n = 718) and were compared to 12,845 stage I-III patients diagnosed in a SEER region. Age, gender, location, stage, number of positive nodes were compared for NCCN and SEER data in regards to number of nodes evaluated. Multivariate logistic regression models were developed to identify factors associated with evaluating 12 LNs. RESULTS: 92% of NCCN and 58% of SEER patients had >or=12 LN evaluated. For patients treated at NCCN centers, factors associated with not meeting the 12 LN target were left-sided tumors, stage I disease and BMI >30. CONCLUSIONS: >or=12 LN are almost always evaluated in NCCN patients. In contrast, this target is achieved in 58% of SEER patients. With longer follow-up of the NCCN cohort we will be able to link this quality metric to patterns of recurrence and survival and thereby better understand whether increasing the number of nodes evaluated is a priority for cancer control.

Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in stage II colon cancer.

BACKGROUND: Failing to meet the benchmark of 12 lymph nodes in resection specimens is an indication for adjuvant chemotherapy in stage II colon cancer. METHODS: Among consecutive eligible patients with pathologic stage II colon cancer treated at eight NCI-designated comprehensive cancer centers between September 1, 2005 and February 19, 2008, we analyzed receipt of adjuvant chemotherapy, with less than 12 versus 12+ lymph nodes removed and examined the primary explanatory variable of interest. RESULTS: Among 258 patients, 46% received adjuvant chemotherapy. An oxaliplatin-containing regimen was used 67% of the time. Younger age (<50 years, P < 0.001), presence of lymphovascular invasion (P = 0.007), and higher T stage (P = 0.007) were independently associated with adjuvant chemotherapy use. There was significant inter-institutional variability in practice with the proportion receiving treatment ranging from 17% to 64% (P < 0.05). Notably, presence of less than 12 lymph nodes in the surgical specimen was a strong predictor of treatment (P = 0.008). CONCLUSIONS: Adjuvant chemotherapy use after resection of stage II colon cancer is common, but by no means standard practice at National Comprehensive Cancer Network (NCCN) institutions. More attention to achieving the recommended benchmark for lymph node dissection has the potential to decrease exposure to the toxicity of adjuvant treatment.

Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients.

PURPOSE: To identify risk factors that might predict for systemic fungal infections in marrow transplant recipients within the first 100 days and to assess the efficacy of low-dose amphotericin B used as prophylaxis for candidemia and infection with invasive Aspergillus species in patients at risk. PATIENTS AND METHODS: A retrospective analysis of transplant outcomes for 331 allogeneic marrow recipients transplanted between 1983 and 1989 was performed to identify patients who might be at increased risk of fungal infection. Factors analyzed included disease, remission status, transplant regimen, graft-versus-host disease (GVHD) prophylaxis, duration of neutropenia, and development of GVHD. A trial of low-dose amphotericin (5 to 10 mg/d) begun on day +1 and continuing for 2 to 3 months posttransplant was begun in 1987 to evaluate its utility in reducing systemic mycoses. RESULTS: There were 18 episodes of candidemia and 18 systemic mycoses documented by blood or tissue culture or by biopsy. The initiation of high-dose (0.5 to 1 mg/kg/d) corticosteroids early as a component of GVHD prophylaxis in 1986 was identified as the most important risk factor for fungal infections, with a sixfold increase in infections as compared with the previous GVHD regimen (P < .0001); this was despite a significant decrease in the incidence of grade II to IV GVHD (7% v 43%; P = .0001). Low-dose amphotericin B initiated before the start of high-dose corticosteroid GVHD prophylaxis reduced the incidence of fungal infections from 30% to 9% (P = .01) without renal toxicity. Cyclosporine levels were lower in the patients who received amphotericin, leading to an increase in the rate of GVHD to 19% (P = .02). Controlling for GVHD prophylaxis, prolonged neutropenia (P = .00), and grade II to IV GVHD (P = .01) were also identified as risk factors for fungal infection. CONCLUSION: Amphotericin B can be used in low doses as prophylaxis for fungal infections early in the posttransplant course. However, cyclosporine doses need to be monitored to maintain target levels.

Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia.

PURPOSE: A non-radiation-containing regimen of busulfan and cyclophosphamide (BU/CY) was evaluated for toxicity, relapse, and long-term survival in patients who received allogeneic bone marrow transplantation (BMT) for myelodysplasia (MDS). PATIENTS AND METHODS: Thirty-eight patients with MDS, including eight with therapy-related MDS, were prepared for BMT using BU/CY. RESULTS: Fourteen patients remain in first remission 18 to 60 months posttransplant. Five patients relapsed after BMT, and four of these patients died. Eight additional patients died of acute or chronic graft-versus-host disease (GVHD), and 11 died of regimen-related toxicity, primarily systemic mycoses. Overall survival rate at 2 years was 45% (95% confidence interval [CI], 0.30 to 0.61), with a 24% probability of relapse (95% CI, 0.10 to 0.49). Regimen-related toxicity was manifested primarily as hepatic dysfunction in 72% of patients, with 16% developing overt venoocclusive disease (VOD). CONCLUSION: Non-radiation-containing preparative regimens offer long-term survival in allogeneic BMT for MDS that is comparable to that of radiation-containing regimens, and are useful in patients with therapy-related MDS. Monitoring BU levels may reduce regimen-related mortality and improve survival.

Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Solid cancers after bone marrow transplantation.

PURPOSE: To evaluate the incidence and associated risk factors of solid cancers after bone marrow transplantation (BMT). PATIENTS AND METHODS: We analyzed 2,129 patients who had undergone BMT for hematologic malignancies at the City of Hope National Medical Center between 1976 and 1998. A retrospective cohort and nested case-control study design were used to evaluate the role of pretransplantation therapeutic exposures and transplant conditioning regimens. RESULTS: Twenty-nine patients developed solid cancers after BMT, which represents a two-fold increase in risk compared with a comparable normal population. The estimated cumulative probability (+/- SE) for development of a solid cancer was 6.1% +/- 1.6% at 10 years. The risk was significantly elevated for liver cancer (standardized incidence ratio [SIR], 27.7; 95% confidence interval [CI], 1.9 to 57.3), cancer of the oral cavity (SIR, 17.4; 95% CI, 6.3 to 34.1), and cervical cancer (SIR, 13.3; 95% CI, 3.5 to 29.6). Each of the two patients with liver cancer had a history of chronic hepatitis C infection. All six patients with squamous cell carcinoma of the skin had chronic graft-versus-host disease. The risk was significantly higher for survivors who were younger than 34 years of age at time of BMT (SIR, 5.3; 95% CI, 2.7 to 8.6). Cancers of the thyroid gland, liver, and oral cavity occurred primarily among patients who received total-body irradiation. CONCLUSION: The risk of radiation-associated solid tumor development after BMT is likely to increase with longer follow-up. This underscores the importance of close monitoring of patients who undergo BMT.

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission.

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients.

Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1-32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.

High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission.

Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.

Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure.

Sickle cell chronic lung disease (SCLD) is a prime contributor to mortality in young adult patients with sickle cell disease, especially those with sickle cell anemia (SS). Both perfusion and diffusion defects have been demonstrated, with generalized pulmonary fibrosis and disabling restrictive lung failure. We report 28 cases (25 SS, 1 S beta(0) thalassemia, 1 S beta(+) thalassemia and 1 SO-Arab) which began during the second decade of life and which ended in death by the fourth decade, after an ordered progression to pulmonary failure and cor pulmonale. Myocardial hypoxia with multifocal fibrosis and segmental infarction occurred in more than one-third of the cases and sudden death was a frequent final event. We define 4 stages of SCLD, based on pulmonary function tests, chest roentgenograms, blood gases, and noninvasive cardiac studies; each stage is 2 or 3 years in length, until death ensues in Stage 4. Case-control analysis showed that the significant risk factors associated with SCLD are 1) the total number of acute chest syndrome events in an individual before the onset of SCLD, (p = 0.0001), 2) sickle cell crisis marked by chest pain (p = 0.03) and 3) aseptic necrosis (p = 0.005). Temporal clustering of acute chest syndrome episodes frequently heralds the onset of SCLD. The pulmonary arterial bed, which has low oxygen tension and low pressure in a slow-flow system, is ideally suited to facilitate the polymerization of sickle hemoglobin, causing endothelial damage and culminating in an obstructive arteriolar vasculopathy. Identification of the significant risk factors predictive of SCLD can lead to early diagnosis of the disease; this is the only hope for effective intervention therapy.

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

Seroepidemiologic studies of cytomegalovirus and Epstein-Barr virus infections in relation to human immunodeficiency virus type 1 infection in selected recipient populations. Transfusion Safety Study Group.

Antibodies to human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were evaluated among 1,171 persons with and without antibodies to human immunodeficiency virus type 1 (anti-HIV-1). These included 97 blood donors, 577 persons given blood components or products, and 497 controls. A significantly higher proportion of anti-HIV-1 positive than -negative donors were anti-CMV-positive, a finding associated with homosexual contact among some of the former. Among subjects with treated clotting disorders, there was no difference in prevalence of anti-CMV or anti-EBV between anti-HIV-1-positive and -negative persons. The prevalence of antibodies to EBV early antigens showed no relationship to anti-HIV-1 status. Anti-CMV positivity in anti-HIV-1-negative donors was associated with an increase in mean CD8 counts and lower mean CD4/CD8 ratio. Anti-CMV and anti-EBV positivity in anti-HIV-1-positive subjects with treated clotting disorders was not associated with a lower CD4 or higher CD8 count than HIV-1 infection alone. Subjects who developed AIDS after enrollment had no significant difference in median time from entry to diagnosis when analyzed by serologic evidence of CMV and EBV antibody status at entry, and a few subjects had AIDS at entry without serologic evidence of prior CMV or EBV infection. The overall results are consistent with acquisition and progression of HIV-1 independently of coincident CMV or EBV infection.

Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life.

A group of 235 allogeneic marrow recipients were contacted at least one year following their BMT to obtain information on their quality of life; 212 (90%) agreed to participate in this survey. A total of 162 adults and 50 pediatric survivors were interviewed during clinic visits (5%) or over the telephone (95%). Changes in productive activity and marital status at the time of interview were studied, as well as the presence of physical symptoms and perception of a general sense of well-being. Older transplant recipients were observed to have a significantly higher incidence of chronic graft-versus-host disease, common colds, and skin changes when compared with pediatric transplant recipients (P < 0.01). Older subjects were also more likely to require any type of regular medication. Younger survivors were rated with a higher Karnofsky performance status and global subjective score. There were no significant differences between patients who received TBI as part of the conditioning regimen and those who did not, with the exception of increased cataract development in pediatric patients receiving TBI (P < 0.008). We conclude that most allogeneic marrow transplant survivors, especially those individuals of younger age at the time of their transplants, are doing well in the domains tested.

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens.

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin's disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose 5-7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (> 5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30-40 Gy at 1.8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease.

Pretransplant pulmonary function predicts cytomegalovirus-associated interstitial pneumonia following bone marrow transplantation.

STUDY OBJECTIVE: To determine the value of pulmonary function tests (PFTs) in predicting the development of human cytomegalovirus (CMV)-associated interstitial pneumonia (IP) in allogeneic bone marrow transplant (BMT) recipients. DESIGN: Nonrandomized, prospective, open-trial study. SETTING: Tertiary referral medical center. PATIENTS: 66 evaluable CMV-seropositive patients with hematologic malignancies who were undergoing allogeneic BMT. INTERVENTION: FEV1, FVC, FEV1/FVC, TLC, Dcoc/VA, PaO2, and P(A-a)O2 were measured on days -13, +33, and +44 following BMT. CMV-IP was diagnosed when typical roentgenographic findings developed with confirmatory positive bronchoalveolar lavage (BAL) using standard cytologic and/or rapid culture techniques. MEASUREMENT AND MAIN RESULTS: Univariate logistic regression analysis to predict the development of CMV-IP revealed significant associations with the day -13 and +33 percent predicted FEV1, FVC, and TLC (p < 0.01) but no associations with other PFT parameters or with changes in these parameters. Stepwise logistic regression analysis demonstrated that only BAL positivity for CMV (odds ratio 14.8; p = 0.0002) and day -13 percent predicted FEV1 (odds ratio 0.92; p = 0.0004) were significant independent predictors of CMV-IP. CONCLUSION: Pretransplant lung function is a previously unrecognized strong predictor and risk factor for the subsequent development of CMV-IP in BMT recipients.

Myeloperoxidase immunoreactivity in adult acute lymphoblastic leukemia.

To evaluate the frequency and significance of myeloperoxidase positivity in adult acute lymphoblastic leukemia (ALL), bone marrow biopsy material from 82 adults with ALL was evaluated with a polyclonal myeloperoxidase (pMPO) antibody. Nineteen cases (23%) demonstrated evidence of pMPO immunoreactivity. Positive cases were precursor B-cell lineage, and CD13 or CD15 expression was more frequent than in the pMPO-negative cases. A subset of pMPO-positive cases studied with a monoclonal MPO antibody was negative. Western blot analysis using the pMPO antibody showed the expected 55-kd band for myeloperoxidase in pMPO-positive and pMPO-negative ALLs, suggesting a lack of specificity of this antibody in ALL. Forty-two percent (8/19) of the pMPO-positive ALL cases demonstrated evidence of t(9;22) by either karyotype or polymerase chain reaction analysis. The pMPO-positive ALLs had a lower frequency of extramedullary disease than the pMPO-negative group and a trend toward improved overall survival compared with the pMPO-negative group. Immunoreactivity with pMPO in adult ALL may lead to an incorrect interpretation of biphenotypic acute leukemia using a recently described scoring system, and a revision to that scoring system is proposed to accommodate pMPO-positive ALL.

Myelodysplastic syndrome occurring after autologous bone marrow transplantation for lymphoma. Morphologic features.

Clonal karyotypic abnormalities characteristic of myelodysplastic syndrome (MDS) occur in up to 18% of patients who undergo autologous bone marrow transplantation (auto-BMT) for the treatment of lymphoma. Morphologic changes are often subtle and may not meet the French-American-British Cooperative Group criteria for MDS. We retrospectively assessed dysplastic changes in peripheral blood and bone marrow specimens obtained before and after transplantation from nine patients and correlated them with karyotype and survival. All patients had normal cytogenetic study results before transplantation and had clonal karyotypic abnormalities develop after auto-BMT. Four patients (with aggressive MDS) survived a short time and died of acute myelogenous leukemia or MDS-related complications, four (with indolent MDS) had a prolonged survival period, and one patient died of recurrent lymphoma. The group with aggressive MDS had significantly more bone marrow trilineage dysplasia before auto-BMT than did the group with indolent MDS or cytogenetically normal auto-BMT controls, suggesting that stem cell damage occurred before transplantation and was not detected by pretransplantation cytogenetic analysis. Comparatively greater dyserythropoiesis and dysmegakaryopoiesis were present after transplantation; these changes were similar to those seen in de novo MDS. Posttransplantation dysplasia in the group with indolent MDS was analogous to the atypia related to the transplantation process.

Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin's lymphoma.

The primary objective of this study was to evaluate the outcome of patients treated with high-dose chemo-/radiotherapy or high-dose chemotherapy and autologous stem-cell transplant (ASCT) for relapsed, refractory, or poor-risk intermediate-grade (IG) and high-grade (HG) non-Hodgkin's lymphoma (NHL). The secondary objectives were to determine prognostic factors for relapse and survival. Between February 1987 and August 1998, 264 patients, 169 (64%) IG and 95 (36%) HG, underwent high-dose therapy and ASCT at City of Hope National Medical Center (COHNMC). There were 157 (59%) males and 107 (41%) females with a median age of 44 years (range, 5-69 years). The median number of prior chemotherapy regimens was 2 (range, 1-4), and 71 (27%) had received prior radiation as part of induction or as salvage therapy. The median time from diagnosis to ASCT was 10.8 months (range, 3-158 months). Ninety-four patients (36%) underwent transplantation in first complete/partial remission (CR/PR), 40 (15%) in induction failure, and 130 (49%) in relapse or subsequent remission. Two preparative regimens were used: total body irradiation/high-dose etoposide/cyclophosphamide (TBI/VP/CY) in 208 patients (79%) and carmustine/etoposide/cyclophosphamide (BCNU/VP/CY) in 56 patients (21%). One hundred sixty-three patients (62%) received peripheral blood stem cells (PBSC) and 101 (38%) received bone marrow (BM) alone or BM plus PBSC. At a median follow-up of 4.43 years for surviving patients (range, 1-12.8 years), the 5-year Kaplan-Meier estimates of probability of overall survival (OS), progression-free survival (PFS), and relapse for all patients are 55% (95% confidence interval [CI]: 49%-61%), 47% (95% CI: 40%-53%), and 47% (95% CI: 40%-54%), respectively. There were 27 deaths (10%) from nonrelapse mortality, including seven (3%) patients who developed second malignancies (five with myelodysplasia/acute myelogenous leukemia and two with solid tumors). By stepwise Cox regression analysis, disease status at ASCT was the only prognostic factor that predicted for both relapse and survival. The 5-year probability of PFS for patients transplanted in first CR/PR was 73% (95% CI: 62%-81%) as compared to 30% (95% CI: 16%-45%) for induction failure and 34% (95% CI: 26%-42%) for relapsed patients. Our results further support the role of high-dose therapy and ASCT during first CR/PR for patients with poor-risk intermediate- and high-grade NHL. Early transplant is recommended for patients failing initial induction therapy or relapsing after chemotherapy-induced remission. Relapse continues to be the most common cause of treatment failure. An alternative approach to prevent relapse, the incorporation of radioimmunotherapy into the high-dose regimen, is being investigated. The development of a second malignancy is a serious complication of high-dose therapy, which requires close surveillance.